This invention is generally in the field of heterocyclic organic molecules that have antibacterial activity.
Bacterial pathogens continue to pose a serious threat to public health as indicated by a worldwide resurgence of bacterial diseases. One aspect of this resurgence appears to be the result of prior widespread, and largely effective, therapeutic and prophylactic use of antibiotics, which, unfortunately, over time has also selected for resistant strains of various bacterial pathogens. Of particular concern to the public health has been the emergence and proliferation of bacterial strains that are resistant to multiple antibiotics in the current arsenal of antimicrobial agents. Such multi-antibiotic resistant (xe2x80x9cMARxe2x80x9d) bacterial strains include species of Gram positive bacteria, such as, antibiotic resistant strains of Staphylococcus aureus, Enterococcus fecalis, and Enterococcus fecium, which, along with antibiotic resistant Gram negative strains of Escherichia coli, constitute the most frequent etiological agents of nosocomial (hospital-acquired) diseases, such as septicemia, endocarditis, and infections of wounds and the urinary tract. S. aureus is currently the most frequent cause of nosocomial bacteremia and skin or wound infection. Streptococcus pneumoniae causes several serious and life-threatening diseases, including a contagious meningitis, bacteremia, and otitis media. Annual mortality from S. pneumoniae infection alone is estimated at between 3-5 million persons globally. More recently, clinical accounts of highly aggressive skin and tissue infections by xe2x80x9cflesh-eatingxe2x80x9d strains of Group A streptococcus bacteria, such as Streptococcus pyogenes, has heightened the concern and need for new or improved antibacterial agents.
Recently, a group of organic compounds has been described which are structural analogs of deoxynucleotides, such as N3-substituted uracil and isocytosine and 9-substituted guanine and adenine compounds. Such compounds have been classified as xe2x80x9cHPUraxe2x80x9d (for xe2x80x9c6-(p-hydroxyphenylazo)uracil)-like class of anti-microbial compounds or the 6-anilinouracil (xe2x80x9cAUxe2x80x9d) family of compounds, which are non-traditional antibiotics in that they specifically bind and inhibit the bacterial DNA polymerase IIIC (xe2x80x9cPol IIICxe2x80x9d) that is required for DNA replication in the xe2x80x9clow G-Cxe2x80x9d eubacteria, which include mycoplasmas and the low G-C, Gram positive bacteria such as Streptococcus, Enterococcus, Staphylococcus, Bacillus, Clostridium, and Listeria (see, e.g., Wright et al., Curr. Opin. Anti-Infective Investig. Drugs, 1: 45-48 (1999); Tarantino et al., J. Med. Chem., 42: 2035-2040 (1999); U.S. Pat. No. 5,516,905). Accordingly, these compounds are antibiotics capable of inhibiting Gram positive bacteria and mycoplasmas (see, e.g., U.S. Pat. No. 5,516,905).
Another approach to developing improved antibiotics has been the synthesis of hybrid molecules, such as the family of hybrid molecules consisting of a fluoroquinolone antibiotic molecule (see, e.g., Domagala et al., J. Med. Chem., 29: 394-404 (1986)) linked to a xcex2-lactam antibiotic molecule (see, e.g., Hamilton-Miller, J. Antimicrobial Chemotherapy, 33: 197-202 (1994)). Such hybrid molecules are xe2x80x9cdual-actionxe2x80x9d antibiotics in that they offer the benefit of a fluoroquinolone component, which can inhibit bacterial type II topoisomerase (Topo II), and a xcex2-lactam component, such as cephalosporins and penicillins, which inhibit bacterial cell wall synthesis (see, e.g, Hamilton-Miller, J. Antimicrobial Chemotherapy, 33: 197-202 (1994)). The fluoroquinolone and xcex2-lactam components may be linked to one another via an ester linkage in a xe2x80x9cpro-drugxe2x80x9d form, which can undergo hydrolysis after administration to an individual (often catalyzed by esterase) to provide the two active component antibiotics. Alternatively, linkages less susceptible to spontaneous hydrolysis may be used to enhance the half-life of the hybrid molecule after administration. In this latter case, the fluoroquinolone active segment may be released in the presence of a xcex2-lactamase, such as produced by P-lactam resistant bacteria, or when the xcex2-lactam antibiotic is acylated during its mode of action (Id.).
A dual-action antibiotic directed against two different targets in a bacterial cell is an attractive strategy as the probability of the appearance of a resistant strain in a treated bacterial population should be quite low, i.e., equal to the product of the probabilities of occurrence of two, spontaneous and separate, resistant mutations in a single bacterial cell. The impact that currently available, hybrid antibiotics, such as the xe2x80x9ccephaloquinsxe2x80x9d (or xe2x80x9cquinocephsxe2x80x9d), as described above, will have clinically remains to be determined. Moreover, as is well known, the search and development of a variety of antibiotics will continue to be necessary as it is unlikely that any one class of antibiotics will be effective against a sufficiently wide spectrum of bacteria as to treat all bacterial diseases or to be used in all patients. Thus, in addition to having an antimicrobial action against one or more clinically significant strains of bacterial pathogens, the successful development of any new and useful antibiotic depends not only on the frequency with which resistant strains may arise, but also on an understanding of such pharmaceutically and pharmacologically relevant properties as solubility, potency, patient toxicity, and the susceptibility of the antibiotic to degradation or clearance when administered to a patient by a particular route.
Clearly, needs remain for compounds that can serve as antibiotics against pathogenic bacterial species as well as for compounds that provide the structural foundation for developing future generations of new anti-microbial agents.
The invention provides a new family of molecules, which are heterocyclic compounds that have antibacterial activity against pathogenic bacterial strains and/or that provide a structural foundation (i.e., are parent molecules) for developing additional new antibacterial agents.
In one embodiment, the invention provides a compound having the formula:
P-L-T, 
wherein P is a segment of the compound that selectively binds and inhibits bacterial DNA polymerase IIIC in the presence of a DNA template and that is linked, directly or indirectly, to segment T of the compound; L is absent or is a linker segment of the compound comprising 1 to 10 atoms in contiguous linear connectivity that links the P and T segments; and T is a segment that is linked, directly or indirectly, to segment P and that selectively inhibits a type II bacterial topoisomerase; and wherein the compound binds and inhibits polymerase IIIC and type II bacterial topoisomerase; and pharmaceutically acceptable salts, esters, and hydrates thereof.
In another embodiment, the invention provides a compound having formula (1) or (2): 
wherein the notation 
signifies an optionally substituted 5-10 membered mono or bicyclic heterocycle in which the ring members are, independently, selected from the group consisting of carbon, nitrogen, sulfur, and oxygen, and wherein any carbon may be optionally substituted with a lower alkyl, amino, carbonyl and thiocarbonyl; and wherein:
A-B is a segment characterized by an ability to selectively bind bacterial type II topoisomerase;
C is absent or a linker segment comprising 1-10 atoms in contiguous linear connectivity;
G is selected from the group consisting of H, aryl, arylalkyl, alkyl, acyl, and an amino protecting group;
Y is absent or selected from the group consisting of lower alkylidene, NH, and CO;
Z is aryl, which may be optionally substituted with alkyl, halo, amino, nitro, acyl, alkylamino, alkylaminoalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, oxo, nitro, hydroxyl, cyano, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclyloxyalkyl, carbocyclylamino, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloyloxyalkyl, heterocyclylamino, and heterocyclylaminoalkyl; and
wherein the segment defined by A-B-C- may be attached at any position of the 5-10 membered mono or bicyclic heterocycle;
and pharmaceutically acceptable salts, esters and hydrates thereof.
In still another embodiment, the invention provides a compound having a formula selected from the group consisting of formulas (3), (4), (5), (6), (7), and (8), as indicated below: 
wherein:
the segment A-B is a pyridone;
C is absent or a linker segment comprising 1-10 atoms in contiguous linear connectivity;
G is selected from the group consisting of H, aryl, arylalkyl, alkyl, acyl, and an amino protecting group;
V is N or a ring carbon substituted with substituent W, wherein W is selected from the group consisting of H, lower alkyl, and halo;
Y is absent or selected from the group consisting of lower alkylidene, NH, and CO;
Z is aryl, which may be optionally substituted with a substituent selected from the group consisting of alkyl, halo, amino, nitro, acyl, alkylamino, alkylaminoalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, oxo, nitro, hydroxyl, cyano, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclyloxyalkyl, carbocyclylamino, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloyloxyalkyl, heterocyclylamino, and heterocyclylaminoalkyl; and
pharmaceutically acceptable salts, esters and hydrates thereof.
In another embodiment, the invention provides a compound of any one of formulas (1)-(8), above, wherein the segment A-B is a pyridone, wherein the pyridone is selected from the group consisting of a 4-quinolone-3-carboxylic acid, 4-pyridone-3-carboxylic acid, 8-aza-4-quinolone-3-carboxylic acid, 6-aza-4-quinolone-3-carboxylic acid, 6,8-diaza-4-quinolone-3-carboxylic acid, 4-quinazolin one-3-carboxylic acid and esters thereof The pyridone may be, e.g., a quinolone. The quinolone may be, e.g., a 6-fluoroquinolone.
The invention also comprises a compound of any one of formulas (1)-(8), wherein the segment A-B- is any one of the radicals of formulas (9), (10), and (11), be low (numbers within rings indicate numbering convention employed): 
wherein
X is N or a ring carbon substituted with substituent R1, wherein R1 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, and aryl;
R2 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, halo, hydroxyl, and saturated or unsaturated 4-10 membered mono or bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from S, N, and O, that may be optionally substituted with one or more alkyl, alkenyl, alkynyl, amino, alkylamino, aminoalkyl, alkylaminoalkyl, or naturally occurring amino acid residues;
R3 is N or a ring carbon substituted with substituent R8, wherein R8 is selected from the group consisting of H, optionally substituted aryl (e.g., unsubstituted or substituted with halo (e.g., F) alkyl (e.g., unsubstituted or substituted with halo), alkenyl, alkynyl, alkoxy, amino, alkylamino, cyano, nitro or halo (e.g., F); or R1 and R8 may be joined to form an optionally substituted, fused 4-8 membered heterocyclic or carbocyclic ring (which may be saturated or unsaturated, or aromatic), wherein the heterocyclic ring comprises 1-3 heteroatoms selected from the group consisting of S, N and O;
R4 is N or a ring carbon substituted with substituent R9, wherein R9 is selected from the group consisting of H, optionally substituted aryl (e.g., unsubstituted or substituted with halo (e.g., F)) alkyl (e.g., unsubstituted or substituted with halo), alkenyl, alkynyl, alkoxy, amino, alkylamino, cyano, nitro or halo (e.g., F); or R2 and R9 may be joined to form an optionally substituted, fused 4-8 membered heterocyclic or carbocyclic ring (which may be saturated or unsaturated, or aromatic), wherein the heterocyclic ring comprises 1-3 heteroatoms selected from the group consisting of S, N and O;
R5 is selected from the group consisting of H, halo, amino (e.g., NH2), alkylamino and lower alkyl (e.g., methyl); and
R6 is N or a ring carbon substituted with substituent R7, wherein R7 is selected from the group consisting of H, halo and lower alkyl; or R1 and R7 may be joined to form an optionally substituted 4-8 membered heterocycle comprising 1-3 heteroatoms selected from the group consisting of S, N, and O.
In one embodiment, compounds of this invention are useful as antibacterial agents. Such compounds inhibit at least bacterial DNA polymerase IIIC (xe2x80x9cPol IIICxe2x80x9d). The compounds of the invention may have a level of inhibitory activity toward bacterial DNA polymerase IIIC that is greater than the level of inhibitory activity of previously known Pol IIIC inhibitor compounds.
In another embodiment, the compounds of this invention inhibit bacterial type II topoisomerase (xe2x80x9cTopo IIxe2x80x9d). Compounds of the invention inhibit both Pol IIIC and Topo II. In another embodiment, compounds of the invention are antibiotics that are effective against one or more species of bacteria, such as species of Gram positive, mycoplasma, and/or Gram negative bacteria. Compounds of the invention are antibiotics that may be effective against one or more species of Gram positive bacteria, such as, without limitation, species of Streptococcus, Enterococcus, Staphylococcus, Bacillus, Clostridium, Listeria, and combinations thereof.
The invention also provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier. Such pharmaceutical compositions may contain one or more other therapeutically active compounds, such as, another antibiotic, anti-viral compound, anti-cancer compound, and the like.
The invention also provides methods of treating bacterial diseases in a patient. Such methods comprise administering a compound of the invention to a patient in need of treatment thereof. The bacterial disease may be caused by a species of mycoplasma or a Gram positive bacteria, including, without limitation, species of Streptococcus, Enterococcus, Staphylococcus, Bacillus, Clostridium, and Listeria.
The invention also provides methods for prophylactic treatment of a bacterial disease comprising administering a compound of the invention to a patient. Such methods are useful when an exact diagnosis cannot or has not been made.
Compounds of the invention may also be used in screening procedures to determine the antibiotic resistance profile of bacterial species of interest.